The gonadotropins, follicle stimulating hormone (FSH), luteinizing hormone (LH), and chorionic gonadotropin (CG) are required for ovulation, spermatogenesis, and the biosynthesis of sex steroids. A single hypothalamic hormone, gonadotropin-releasing hormone (GnRH) also known as LHRH is responsible for regulating the secretion of both FSH and LH in mammals.
LHRH is a decapeptide having the structure:
pyro-Glu.sup.1 -His.sup.2 -Trp.sup.3 -Ser.sup.4 -Tyr.sup.5 -Gly.sup.6 -Leu.sup.7 -Arg.sup.8 -Pro.sup.9 -Gly.sup.10 -NH.sub.2
where the superscripts designate the position of each aminoacyl residue in the decapeptide chain.
LHRH is released from the hypothalamus and binds to a receptor on the pituitary gland, causing the release of LH and FSH which subsequently act on the gonads to stimulate the synthesis of steroid sex hormones. The pulsatile release of LHRH, and thereby the release of LH and FSH, controls the reproductive cycle in animals and humans. Acute doses of LHRH agonists increase the levels of LH and steroidal sex hormones in both animals and humans. Paradoxically, chronic doses of LHRH agonists suppress the level of LH and steroidal sex hormones. Consequently, the effect of multiple doses of LHRH agonists is to suppress estrogen formation in females and testosterone production in males. The same effect is observed in both animals and humans after administration of either acute or chronic doses of LHRH antagonists.
In recent years, considerable research effort has been expended on finding antagonists of LHRH. These efforts have produced a number of peptide LHRH antagonists, which suppress LH and reproductive hormones in mammals upon acute or chronic administrations. See for example, M. J. Karten in "Modes of Action of GnRH and GnRH analogs", edited by W. F. Crowley and P. M. Conn, p. 277 (1992). The literature has reported that LHRH antagonists are useful in the treatment of a variety of conditions in which the suppression of sex steroids plays a key role including contraception, delay of puberty, treatment of benign prostatic hyperplasia, palliative treatment or remission of hormonal-dependent tumors of the prostate, the treatment of cryptorchidism, hirsutism in women, gastric motility disorders, dysmenorrhea, and endometriosis.
Current LHRH antagonists are decapeptides which, because of their low oral bioavailability, are administered either intravenously or subcutaneously. Non-peptide heterocyclic antagonists have been reported in the literature, see for example, WO 95/29900, WO 97/22707, and WO 97/21704. Non-peptide LHRH antagonists have the possible advantage of improved oral bioavailability and are smaller molecules.
However, there are no known reports of macrolide compounds as LHRH antagonists in the literature. Macrolide antibiotics and macrolide prokinetic agents are known. For example, macrolide antibiotics derived from erythromycin which contain 11,12-cyclic carbamate moieties are disclosed in EP 248 279 A2. The 3'-N substituted erythromycin derivatives, which are effective antibacterial agents, are described in EP 0 559 896 A1. Macrocyclic lactone (macrolide) prokinetic agents are known. See J. S. Gidda et al., in European Patent Application No. 0349100, published Jan. 3, 1990, which discloses 12-membered macrolides for use as gastrointestinal motility enhancers. S. Omura and Z. Itoh, in U.S. Pat. No. 4,677,097, issued Jun. 30, 1987; European Application No. 215,355, published Mar. 25, 1987; and European Application No. 213,617, published Mar. 11, 1987; disclose derivatives of erythromycins A, B, C and D which are useful as stimulants of digestive tract contractile motion. Additionally, T. Sunazuka, et al., Chem. Pharm. Bull. 37(10): 2701-2709 (1989) discloses quaternary derivatives of 8,9-anhydroerythromycin A 6,9-hemiacetal and 9,9-dihydro-erythromycin A 6,9-epoxide with gastrointestinal motor stimulating activity.
U.S. application Ser. Nos. 09/049,458, and 09/049,963, now U.S. Pat. No. 5,955,440, filed Mar. 27, 1998, disclose 3'-N-desmethyl-3'-N-substituted-6-O-methyl-11-deoxy-11,12-cyclic carbamate erythromycin A derivatives, which are effective as LHRH antagonists.
However, there is a continuing need to develop new compounds that are effective as LHRH antagonists.